Candotti, F, Shaw, KL, Muul, L, Carbonaro, D, Sokolic, R, Choi, C et al.. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood 120: 3635-3646

Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
Blood (Impact Factor: 10.45). 09/2012; 120(18). DOI: 10.1182/blood-2012-02-400937
Source: PubMed


We conducted a gene therapy trial in 10 patients with adenosine deaminase-deficient severe combined immunodeficiency (ADA-deficient SCID) using two slightly different retroviral vectors for the transduction of patients' bone marrow CD34+ cells. Four subjects were treated without pre-transplant cytoreduction and remained on ADA enzyme replacement therapy (ERT) throughout the procedure. Only transient (months), low level (<0.01%) gene marking was seen in peripheral blood mononuclear cells (PBMC) of two older subjects (15 and 20 years old), whereas some gene marking of PBMC has persisted for the past nine years in two younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years post-procedure), with gene marking in PBMC of 1-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT due to poor gene marking and immune recovery and one had a subsequent allogeneic hematopoietic stem cell transplant. These studies directly demonstrate the importance of providing non-myeloablative pre-transplant conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient SCID.

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Available from: Kit L. Shaw, Apr 04, 2014
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    • "The earliest gene therapy trials focused on combined immune deficiencies, using correction of gene defects in hematopoietic stem cells (HSCs), and there have been notable clinical successes reported in multiple trials for adenosine deaminase deficiency–severe combined immunodeficiency (ADA-SCID) (Candotti et al., 2012) and for X-linked severe combined immunodeficiency (Hacein-Bey-Abina et al., 2010), although for the latter this clinical success came with an unacceptable rate of vector-driven hematologic malignancy. Dr. Satiro De Oliveira, University of California–Los Angeles reviewed the uses of CD34 + HSCs transduced ex vivo with vectors to deliver transgenes for immunodeficiencies (Aiuti et al., 2009; Hacein-Bey-Abina et al., 2010; Booth et al., 2011), sickle cell disease (Romero et al., 2013), and b thalassemia, and the potential to use such cells in cancer immunotherapy (e.g., for gene modified T-cell receptors, or CARs) (De Oliveira et al., 2013; Giannoni et al., 2013). "
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    ABSTRACT: Recently, the gene therapy field has begun to experience clinical successes in a number of different diseases using various approaches and vectors. The Gene Therapy: Charting a Future Course workshop, sponsored by the National Institutes of Health (NIH) Office of Biotechnology Activities, brought together early and mid-career researchers to discuss the key scientific challenges and opportunities, ethical and communication issues, and NIH and foundation resources available to facilitate further clinical advances.
    Human gene therapy 04/2014; 25(6). DOI:10.1089/hum.2014.045 · 3.76 Impact Factor
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    • "This regimen must balance safety in a nonmalignant population with the requirement for efficient engraftment. Busulfan-based conditioning regimens have been used in clinical trials of gene therapy for the correction of human genetic diseases, including adenosine deaminase deficiency SCID [49, 50•] and X-linked CGD [51]. The safety of busulfan in HIV/AIDS patients remains to be determined in 2 currently active trials (NCT01734850 and NCT01961063). "
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    ABSTRACT: Despite the success of antiretroviral therapy in suppressing HIV-1 replication and extending the life of HIV-1 infected individuals, this regimen is associated with risks for non-AIDS morbidity and mortality, requires life commitment, and has a high cost. In this context, gene therapy approaches that have the potential to cure HIV-1 infection present a clear option for eradication of the virus in the next decades. Gene therapy must overcome concerns related to its applicability to HIV-1 infection, the safety of cytotoxic conditioning required for cell-based approaches, clinical trial design, selection of gene-modified cells, and the restrictive cost of manufacturing and technology. These concerns are discussed herein in the context of the most relevant gene therapy studies conducted so far in HIV/AIDS.
    Current HIV/AIDS Reports 01/2014; 11(1). DOI:10.1007/s11904-013-0197-1 · 3.80 Impact Factor
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    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2012; 19(1). DOI:10.1016/j.bbmt.2012.09.021 · 3.40 Impact Factor
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